Abbreviations

WHO — World Health Organization

ACTH — adrenocorticotropic hormone

DM — dura mater

DNA — deoxyribonucleic acid

Pituitary adenomas account 10—15% of intracranial neoplasms [1]. According to the 2004 WHO classification, pituitary adenomas are divided into typical, atypical and adenocarcinomas [2]. Typical pituitary adenomas are characterized by monomorphic cells and absence of high mitotic activity, Ki-67 index over 3% and/or immunopositive p53. According to the WHO classification, which was in force before the introduction of the 2017 classification, atypical pituitary adenomas with the above characteristics were distinguished [2]. Incidence of atypical adenomas is 2—15% if above-mentioned criteria are applied. However, prognostic value of this classification has not been established over 10-year existence [3—5]. Therefore, the term “atypical adenoma” is no longer used in the 2017 WHO classification for these reasons [6]. Certain subtypes of pituitary neuroendocrine tumors in the new classification are distinguished as “high-risk” pituitary adenomas due to aggressive course that is evidenced by several clinical trials [7, 8]. These tumors include somatotropinomas, prolactinomas in men, corticotropinomas such as Crooke's cell adenoma, latent corticotropinomas associated with elevated level of ACTH and cortisol and no clinical signs of Cushing's disease and recently identified plurihormonal Pit-1-positive adenoma (pituitary adenoma subtype 3) [6].

According to current classification, adenocarcinomas are pituitary tumors which can metastasize. Incidence of these neoplasms is extremely low (near 0.2% of all pituitary tumors) [9].

According to various data, pituitary adenomas are characterized by invasive growth and invasion of surrounding structures (sphenoid sinus, cavernous sinus, etc.) in 25—55% of cases [10—14]. Moreover, tumor growth is not obligatory associated with atypical nature, since atypical pituitary adenomas grow invasively and non-invasively [15]. For example, Liu J. et al. reported that some pituitary adenomas with invasive growth are relatively benign with Ki-67 index <3% and no other signs of aggressive course. At the same time, other pituitary adenomas with invasive growth are recognized as atypical due to Ki-67 index over 3%, resistance to conventional therapy including temozolomide and frequent recurrences [16].

Aggressiveness

Some specific types of endocrine-active pituitary tumors may be characterized by more aggressive course. Pituitary tumors consisting of ACTH-releasing cells (Crooke’s cells), as well as endocrine-active pituitary adenomas may have aggressive course regarding recurrence rate and invasiveness [3, 17—21]. However, there is no complete clarity in definition of “aggressive pituitary adenoma”, since potential biomarkers determining aggressiveness of pituitary adenoma including chromosomal and miRNA changes, proliferation markers, oncogenes, tumor suppressor genes, growth factors and their receptors, factors of angiogenesis or cellular adhesion are not identified [15, 22]. As a result, tumor is classified as aggressive adenoma considering only invasiveness and growth rate, large dimension, resistance to conventional therapy and frequent recurrences [2, 10, 18].

According to some reports, aggressiveness of pituitary adenoma may be associated with latent release of hormones (ACTH, growth hormone, TSH), change of immunophenotype and increased proliferation index (>15%). However, aggressive growth and recurrence rate are observed without these signs in some cases [23].

Moreover, aggressiveness of some pituitary adenomas with invasive growth is often unnoticed due to histological data on benign nature of tumor [24]. At the same time, microscopic invasion of, for example, dura mater cannot be considered as sign of aggressiveness due to high incidence of this finding [12—14].

Thus, there is classification of adenomas into typical and atypical, invasive and non-invasive, aggressive and non-aggressive. However, it is still unclear what category includes malignancies without cerebrospinal and/or systemic metastases and characterized by significant growth rates, high Ki-67 values, recurrence rate, resistance to conventional therapy and unfavorable outcome [25]. In 2016, Congxin Dai et al. proposed the term “refractory pituitary adenoma” to identify these tumors [25]. Diagnostic criteria were: 1) invasive growth confirmed by radiological or intraoperative data; 2) Ki-67 index over 3% with growth rate over 2% per month; 3) ineffective therapeutic control of tumor growth and/or hormone release; 4) recurrence of tumor within 6 months after surgery; 5) no metastases.

Molecular features

Molecular examinations confirm that pituitary tumors accumulate various chemical abnormalities in cells over time that contributes to their progression from “benign” adenoma to aggressive recurrent pituitary tumors and, in extremely rare cases, pituitary carcinoma [2, 26]. Some molecular markers correlate with aggressive course of pituitary tumors. One of them is truncated form of fibroblast growth factor receptor 4 (FGFR4). This marker induces invasion of pituitary tumor in experimental models in vivo in combination with reduced expression of membrane N-cadherin [21]. Kawamoto H. et al. found higher level of metalloproteinase-9 (MMP9) in invasive tumors compared with non-invasive pituitary neoplasms [27].

As new molecular markers of proliferation and invasion appear, more detailed histological typing of pituitary tumors will be possible considering Ki-67 and p53 with additional inclusion of FGFR4, MMP9 and determination of deletions in chromosome 11p [28]. However, this concept has not yet been tested. It is also unclear whether the expanded diagnostic testing of specimens for better prediction of aggressive course of tumors and optimization of treatment of these patients will be implemented [9].

Treatment

Treatment should be carried out under supervision of multidisciplinary team including neurosurgeon, radiologist, oncologist, endocrinologist and ophthalmologist if aggressive pituitary adenoma is suspected [29]. However, standard definition of aggressive pituitary adenoma is still absent. Therefore, there are no studies devoted to optimal therapy of these patients except for several reports describing administration of temozolomide as palliative therapy [30—32].

Resection of aggressive pituitary adenomas reduces tumor volume and compression of surrounding structures [33, 34]. Moreover, even partial resection of tumor can ensure decompression of irradiation-sensitive structures, for example, optic chiasm and safer subsequent irradiation of this zone [9]. Vroonen L. et al. reported higher susceptibility of previously resistant tumors to conservative therapy after surgical resection [35].

Irradiation

Radiotherapy is the next step of treatment in case of early postoperative continued growth or recurrence rather surgical and conservative approaches.

High-dose stereotactic irradiation, especially in radiosurgery mode, ensures good efficiency and is convenient for patients. Hypo- or standard fractionation mode is recommended if tumor is close to irradiation-sensitive structures [36, 37].

Analysis of the effectiveness of radiotherapy may be difficult due to the use of various focal single and total radiation doses [38]. According to various data, effectiveness of radiotherapy varies from 67 to 100% [39].

Both stereotactic and fractionated radiotherapy can ensure cytostatic effect and lead to decrease of tumor volume in some cases [38]. The best response to radiotherapy is typical for small tumors and risk of hypopituitarism associated with treatment is lower. Unlike the number of surgeries, the number of radiotherapy courses is limited due to the risk of irradiation-induced necrosis of surrounding structures. This complication is followed by panhypopituitarism, impaired vision and damage to the temporal and frontal lobes [40, 41].

Chemotherapy

Various chemotherapy protocols were applied for the treatment of aggressive pituitary adenomas. However, none of these approaches showed promising results [42]. The lack of response to standard chemotherapy may be due to relatively low proliferation rate of aggressive pituitary adenomas, i.e. these neoplasms retain certain features of highly-differentiated tumors [43].

Only temozolomide has shown certain effectiveness in the treatment of aggressive pituitary adenomas [44]. The efficacy of combination of capecitabine and temozolomide was also observed in a sample of 3 patients [45].

Temozolomide is a second-generation alkylating agent. Cytotoxic effect is determined by guanine methylation in O-6 position of DNA. This process disrupts its pairing with thymine in the next DNA replication cycle. Methylguanine methyltransferase (MGMT) is a DNA repair enzyme that counteracts the action of temozolomide by removal of alkylating molecules [46]. Thus, expression of MGMT by pituitary adenoma can theoretically predict the response to the treatment. However, temozolomide is still used regardless of MGMT expression since this assumption has not been conclusively confirmed [9, 31, 47].

Temozolomide is currently used for various pituitary adenomas including bromocriptine- or cabergoline-resistant prolactinomas, ACTH-releasing adenomas, especially Crooke’s cell adenomas, recurrent endocrine-inactive pituitary adenomas with continued growth after redo surgery and radiotherapy [48]. Response to therapy in these cases is probably ensured by low expression of MGMT followed by enhanced toxic effect of temozolomide [49].

Standard chemotherapy mode with temozolomide is usually used: 150—200 mg/m2 for 5 days every 28 days [50]. The effect of chemotherapy is assessed considering clinical, neuroimaging and morphological data [50] (hemorrhage inside the tumor, necrosis, focal fibrosis, inflammatory infiltration, reduced number of mitoses, lower Ki-67 index [51]). Therapeutic effect including reduced tumor volume and endocrine secretion is usually observed in 3 months after onset of therapy with temozolomide [44].

Prolonged administration of alkylating agents, such as Temozolomide, is associated with increased risk of secondary malignancies (especially leukemia and lymphoma). Currently, it is unclear what approach will ensure the best efficacy of treatment without increased risk of secondary malignancies [52]. Another unclear question is devoted to administration of temozolomide alone or in combination with other drugs, such as pasireotide or capecitabine [45, 53].

Temozolomide was previously used only for the treatment of glioblastomas, melanomas and neuroendocrine tumors [54, 55]. The first successful treatment of pituitary adenomas with this drug was shown in the management of prolactin-releasing carcinomas in 2006 [56]. Some retrospective trials with sample size from 5 to 33 patients showed low efficacy of temozolomide therapy over the past few years and emphasized the absence of standards and protocols for prescription of this drug [44, 57, 58].

According to various authors, incidence of positive response to the therapy varies from 29 to 81% depending on response criteria [57, 58].

Comparison of published studies is significantly difficult due to different criteria of therapeutic response in all trials. For example, Lasolle H. et al. consider significant decrease of endocrine activity and tumor dimension as the criteria of therapeutic response [59—61]. Other authors recognize tumor dimension stability as a sign of positive therapeutic response [43].

Lasolle H. (2017) reported 3-year survival of 50.3% after completion of temozolomide therapy. However, recurrence occurred in 50% of patients (50%) with positive therapeutic response in 15 (0—57) months after temozolomide therapy. Those patients without recurrence were followed-up only within 9.5 (0—27) months. Higher recurrence rate would be observed during longer follow-up period [43]. Similar data were reported by Bengtsson H. et al. (3-year survival rate of 51.2%). They used similar response criteria [58]. Treatment outcomes in various series of patients are shown in Table.

Prognostic significance of MGMT expression is also controversial issue. Lasolle H. analyzed 43 patients and did not find correlation of MGMT expression and therapeutic response. However, Bengtsson H. reported significantly lower MGMT expression in patients with positive therapeutic response (median 9% (5—20%)) compared with the absence of therapeutic response (median 93% (50—100%)) [58].

Losa M. reported overall 4-year survival of 59.6% after temozolomide therapy with median follow-up of 41 months [62].

Certain issues including duration of treatment, treatment of resistant or unresponsive patients or those with transformation of pituitary adenoma to carcinoma after temozolomide therapy are still unresolved [48].